Inflammation is a component of the pathogenesis of a number of human diseases, as well as a result of physical, chemical or traumatic damage (i.e., inflammation is the response of living tissue to damage). In general, the inflammatory response results in the systemic release of endogenous chemical mediators, which cause vasodilatation, emigration of neutrophils, chemotaxis, and increased vascular permeability. The changes that result from an inflammatory response are essentially the same, regardless of the cause and regardless of where the insult arises. The inflammatory response may be acute (short lived) or chronic (longer lasting).
The development of inflammatory reactions is controlled by cytokines, by products of the plasma enzyme systems (complement, coagulation, kinin, and fibrinolytic pathways), by lipid mediators (prostaglandins and leukotrienes) released from different cells, and by vasoactive mediators released from mast cells, basophils and platelets. Fast-acting mediators, such as vasoactive amines and the products of the kinin system, modulate the immediate response. Later, newly synthesized mediators such as leukotrienes are involved in the accumulation and activation of other cells. Once leukocytes have arrived at a site of inflammation, they release mediators that control the later accumulation and activation of other cells. Thus, the cytokine system is clearly important for homeostasis when cytokine activation is local (i.e., acting nearby as a surface-bound or diffusible form), but when cytokine production is sustained and/or systemic, there is no doubt that cytokines contribute to the signs, symptoms, and pathology of inflammatory, infectious, autoimmune, and malignant diseases.
Typically, an inflammatory response is beneficial because the site of inflammation will have increased access to nutrients, oxygen, antibodies and therapeutic drugs, as well as increased fibrin formation, dilution of toxins, and stimulation of an immune response. However, an inflammatory response may have negative consequences, such as tissue damage caused by the release of lysosomal enzymes by inflammatory cells (neutrophils and macrophages) or an inappropriate response may result in a life threatening hypersensitivity reaction (e.g., asthma or anaphylaxis).
Accordingly, such detrimental inflammatory responses (often referred to as inflammatory diseases) are often treated with anti-inflammatory drugs. There are two major types of anti-inflammatory drugs, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). However, a detrimental consequence of therapies with corticosteroids and NSAIDs is an inhibition of neutrophil function and a reduction in pathogen killing, which can be particularly dangerous in, for example, an immunocompromised patient. In another example, many people suffer the symptoms of Cushing's syndrome as a side effect of taking corticosteroids for asthma, rheumatoid arthritis, lupus, or other inflammatory diseases. Similarly, NSAIDs have side effects, such as causing anaphylactoid reactions and causing gastrointestinal toxicity.
Therefore, a need exists for identifying agents having anti-inflammatory activity that are not immunosuppressive and/or cause other undesirable side effects. Furthermore, there is a need for agents having both antimicrobial activity and anti-inflammatory activity for use in treating, preventing, or ameliorating infectious diseases where concomitant inflammation is a problem, such as in acne vulgaris. Such agents would be useful in a variety of clinical indications having an inflammatory component. The present invention meets such needs, and further provides other related advantages.